What question did this study set out to answer?

To evaluate the functional and pharmacokinetic consequences of engineering a humanized IgG1 antibody with mutations that enhance affinity for the neonatal Fc receptor.

June 23, 2006Journal of Biological ChemistryOpen Access

Properties of Human IgG1s Engineered for Enhanced Binding to the Neonatal Fc Receptor (FcRn)

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To evaluate the functional and pharmacokinetic consequences of engineering a humanized IgG1 antibody with mutations that enhance affinity for the neonatal Fc receptor.
Engineered the triple mutation M252Y/S254T/T256E (YTE) into the Fc domain of the humanized anti-respiratory syncytial virus (RSV) monoclonal antibody MEDI-524.
Assessed pH-dependent binding to human and cynomolgus monkey FcRn, in vitro RSV neutralization, and antibody-dependent cell-mediated cytotoxicity (ADCC).
Measured in vivo serum pharmacokinetics, terminal half-life, and lung tissue bioavailability in cynomolgus monkeys.
The YTE substitution produced a 10-fold increase in binding affinity to both cynomolgus and human FcRn at pH 6.0 with normal release at pH 7.4, without altering antigen binding or viral neutralization.
MEDI-524-YTE achieved a nearly 4-fold increase in serum half-life and up to a 4-fold increase in lung bioavailability compared to unmodified MEDI-524 in cynomolgus monkeys.
The YTE modification effectively modulated ADCC activity when tested on an anti-integrin alpha(v)beta3 humanized IgG1.

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Implication

Preclinical study demonstrates that engineered FcRn-binding IgG1 extends antibody serum half-life nearly fourfold in cynomolgus monkeys, indicating a route to long-acting therapeutic antibodies.

Cite This Study

Dall’Acqua et al. (2006) studied this question.

synapsesocial.com/papers/69d83bc3f4e559c61eae3157 https://doi.org/10.1074/jbc.m604292200

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Implication

Preclinical study demonstrates that engineered FcRn-binding IgG1 extends antibody serum half-life nearly fourfold in cynomolgus monkeys, indicating a route to long-acting therapeutic antibodies.

Properties of Human IgG1s Engineered for Enhanced Binding to the Neonatal Fc Receptor (FcRn)

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Discussion

Implication

Cite This Study

Properties of Human IgG1s Engineered for Enhanced Binding to the Neonatal Fc Receptor (FcRn)

Key Points

Discussion

Implication

Cite This Study

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